Project description
Alzheimer’s disease: the balance between homeostasis and plasticity in the hippocampus
Homeostasis is one of the most important guiding principles of physiological systems. It is a self-regulating process by which biological systems maintain a relatively constant internal environment, adapting to changing environmental conditions to do so. Homeostasis applies to the brain but there must be a balance between stability and the ability to change – plasticity – to subserve functions including learning and memory, largely associated with an area of the brain called the hippocampus. The ERC-funded DormantAD project will evaluate the hypothesis that homeostatic failures destabilise network activity in Alzheimer's disease, using a variety of high-tech tools addressing hippocampal mechanisms from the molecular to the brain state level.
Objective
Neuronal circuits must balance stability and plasticity. How this balance is compromised in brain disorders remains one of the most fundamental questions in neuroscience. Pioneering studies in the field established that homeostatic mechanisms stabilize the function of a system at a set-point level of activity. Recently, we have identified bona fide mitochondrial regulator of activity set points and provided support to our standing hypothesis that homeostatic failures destabilize network activity in Alzheimer's disease (AD). However, we have just scratched the surface of the mechanisms stabilizing activity set points in vivo.
I propose a conceptual and experimental framework to identify the cellular-molecular and circuit-wide in vivo mechanisms underlying stability of hippocampal circuits across distinct brain states and stability-plasticity balance. Using a wide range of optical, electrophysiological, computational and molecular tools, we will explore homeostatic regulation of activity in hippocampal circuitry, a crucial substrate for memory formation, and its relation to AD. First, we will establish governing principles of homeostatic regulation in physiological context of sleep and learning. Next, we will explore the underlying molecular drivers of homeostatic regulation. Finally, we will test the causal relationship between dyshomeostasis of activity in hippocampal circuits, sleep disturbances and cognitive decline in AD models.
To target these questions, we will utilize the basic concepts of control theory and an integrative approach which spans brain-state, neural circuit, synaptic and molecular levels. We believe that this understanding is an essential step to uncover the principle basis underlying the transition from a presymptomatic disease stage to clinically evident cognitive AD impairments. The proposed research will elucidate fundamental principles of neuronal function and reveal conceptually novel insights into how to maintain AD in a dormant state.
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
69978 Tel Aviv
Israel